1. Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: Putting Guidelines into Practice — INTRODUCTION — McMurray J, Cohen-Solal A, Dietz R, Eichhorn E, Erhardt L, Hobbs R, Maggioni A, Pina I, Soler-Soler J, Swedberg K Eur J Heart Failure 2001;3:495–502

2. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — INTRODUCTION — A number of large, carefully designed clinical outcome trials have been conducted in patients with chronic heart failure The trials were sufficiently powered to allow unequivocal interpretation of the results Consequently, there now exists robust safety and efficacy information on a number of therapeutic interventions The translation of these results into clinical prescribing has been slow and incomplete Patients may therefore be denied the full benefit of proven therapeutic interventions

3. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — INTRODUCTION — Development of Recommendations The speed and extent of update of evidence-based therapies (particularly ACE inhibitors and beta-blockers) for the treatment of heart failure has been disappointing in hospital practice and primary care This may reflect a lack of practical advice regarding dosing issues and the management of associated adverse events Consequently, a group of eminent clinicians with expertise in the management of heart failure met during 2000 The remit of the faculty was to review all the relevant published clinical trials and produce a set of clinical recommendations independent of any other interests

4. Practical Recommendations for in Heart Failure Treatment: Putting Guidelines into Practice — INTRODUCTION — Advisory Group John McMurray Glasgow, UK Alain Cohen-SolalClichy, France Rainer DietzBerlin, Germany Eric EichhornDallas, USA Leif Erhardt Malmö, Sweden Richard HobbsBirmingham, UK Aldo MaggioniFlorence, Italy Ileana PinaCleveland, USA Jordi Soler-SolerBarcelona, Spain Karl SwedbergGöteborg, Sweden

5. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — INTRODUCTION — Output The output from discussions was a step-wise, concise set of clinical recommendations concentrating on three key therapies for the management of heart failure These recommendations are not meant to replace existing guidelines, but rather provide a tool to facilitate their implementation The opinions expressed are those of the faculty members and do not necessarily reflect the views of AstraZeneca or the manufacturers of the products mentioned Prescribers need to be aware of the relevant product prescribing information which applies in their country The costs associated with the Advisory Group meetings were met by an educational grant from AstraZeneca

6. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — INTRODUCTION — Format The practical recommendations for treatment are reviewed under the following headings:  Why? – what evidence exists to support the use of these treatments  In whom and when? – which patients, what contra-indications, what cautions and drug interactions  Where? – hospital or primary care setting  Which agent and what dose? – options offered based on outcome evidence  How to use – titration and monitoring information  Advice to patient – expected benefits and drawbacks  Problem solving – management of adverse events and concomitant medications

7. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — INTRODUCTION — Practical Recommendations These recommendations start from the assumption that the physician has made a clinical diagnosis of heart failure and may have initiated diuretic treatment for treating the symptoms and signs associated with fluid overload STEP 1 - Confirm left ventricular systolic dysfunction (LVSD) by echocardiography, radionuclide ventriculography or radiological left ventricular angiography. [These investigations are regarded as definitive and must be regarded as representing the minimum standard of care.]

8. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — INTRODUCTION — Practical Recommendations STEP 2 - Initiate first-line therapy in all patients with heart failure due to LVSD with an ACE inhibitor for NYHA class I-IV and a beta-blocker for NYHA class II-III, unless these are contra-indicated. - Initiate ACE inhibitor first, followed by beta-blocker, both initially at low doses and then up-titrate slowly to the target doses used in the clinical trials, check tolerability and blood chemistry. STEP 3 -Initiate second-line therapy in patients with persistent signs and symptoms of heart failure (NYHA class III/IV) with spironolactone and digoxin; contra-indications and cautions should be observed. - Initiate spironolactone first followed by digoxin, both at a low dose and then up- titrate, check tolerability and blood chemistry.

9. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — INTRODUCTION — ‘The preparation of these concise and practical clinical recommendations for the prescribing of ACE inhibitors and beta-blockers should provide doctors with the confidence to practise evidence-based medicine in their patients with chronic heart failure. This would improve not only the outcomes for the individual patient but also reduce the burden on healthcare systems.’ McMurray J, Cohen-Solal A, Dietz R, Eichhorn E, Erhardt L, Hobbs R, Maggioni A, Pina I, Soler-Soler J, Swedberg K Eur J Heart Failure 2001;3:495–502

10. Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: Putting Guidelines into Practice — ACE INHIBITORS — McMurray J, Cohen-Solal A, Dietz R, Eichhorn E, Erhardt L, Hobbs R, Maggioni A, Pina I, Soler-Soler J, Swedberg K Eur J Heart Failure 2001;3:495–502

11. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — Format The practical recommendations for treatment are reviewed under the following headings:  Why? – what evidence exists to support the use of these treatments  In whom and when? – which patients, what contra-indications, what cautions and drug interactions  Where? – hospital or primary care setting  Which agent and what dose? – options offered based on outcome evidence  How to use – titration and monitoring information  Advice to patient – expected benefits and drawbacks  Problem solving – management of adverse events and concomitant medications

12. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – Why? CONSENSUS I, the SOLVD-treatment study and a meta-analysis of smaller trials showed conclusively that ACE inhibitors increase survival, reduce hospital admissions and improve NYHA class and quality of life in patients with all grades of symptomatic heart failure ATLAS showed clinically important advantages with higher doses of ACE inhibitors in heart failure SAVE, AIRE and TRACE showed that ACE inhibitors increase survival in patients with systolic dysfunction after acute myocardial infarction SOLVD-prevention study showed that ACE inhibitors delay or prevent the development of symptomatic heart failure in patients with asymptomatic LVSD

13. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — SS Co-operative North Scandinavian Enalapril Survival Study I – CONSENSUS I CONSENSUS Trial Study Group N Engl J Med 1987;316:1429–1435

14. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — Studies of Left Ventricular Dysfunction – SOLVD (Treatment Study) SOLVD Investigators N Engl J Med 1991;325:293–302

15. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — Assessment of Treatment with Lisinopril and Survival Study ATLAS Event- free* survival High-dose % Low-dose 0612182430364248 0 25 50 75 100 Follow-up (months) *Combined all-cause mortality plus all-cause hospitalisations Risk reduction 12% p=0.002

16. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – In Whom and When? Indications: Potentially all patients with heart failure First-line treatment (along with beta-blockers) in NYHA class I–IV heart failure Contra-indications: History of angioneurotic oedema Cautions/seek specialist advice: Significant renal dysfunction (creatinine >2.5 mg/dL or 221 µmol/L) or hyperkalaemia (K + >5.0 mmol/L) Symptomatic or severe asymptomatic hypotension (SBP <90 mmHg) Drug interactions to look out for: K + supplements/ K + sparing diuretics (including spironolactone) NSAIDs* AT 1 -receptor blockers *avoid unless essential

17. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – Where?  In the community for most patients  Exceptions – see CAUTIONS/SPECIALIST ADVICE

18. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – Which and What Dose? Starting dose Target dose captopril 6.25 mg tds50–100 mg tds enalapril 2.5 mg bd10–20 mg bd lisinopril 2.5–5 mg od30–35 mg od ramipril 2.5 mg od5 mg bd/10 mg od trandolapril 1 mg od4 mg od od = once daily; bd = twice daily; tds = thrice daily

19. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – How to Use Start with a low dose Double dose at not less than two weekly intervals Aim for target dose or, failing that, the highest tolerated dose Remember some ACE inhibitor is better than no ACE inhibitor Monitor blood chemistry (urea, creatinine, K + ) and blood pressure When to stop up-titration/down-titration – see PROBLEM SOLVING

20. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – Advice to Patient Explain expected benefits (see WHY?) Treatment is given to improve symptoms, to prevent worsening of heart failure and to increase survival Symptoms improve within a few weeks to a few months Advise patients to report principal adverse effects (i.e. dizziness/symptomatic hypotension, cough)

21. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – Problem Solving Asymptomatic low blood pressure: Does not usually require any change in therapy Symptomatic hypotension: If dizziness, light-headedness and/or confusion and low blood pressure occur, reconsider need for nitrates, calcium channel blockers* and other vasodilators If no signs/symptoms of congestion, consider reducing diuretic dose If these measures do not solve the problem, seek specialist advice *calcium channel blockers should be discontinued unless absolutely essential (e.g. for angina or hypertension)

22. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – Problem Solving (continued) Cough: Cough is common in patients with heart failure, many of whom have smoking-related lung disease Cough is also a symptom of pulmonary oedema, which should be excluded if a new or worsening cough develops ACE inhibitor-induced cough rarely requires treatment discontinuation If a very troublesome cough develops (e.g. one stopping the patient sleeping) and can be proven to be due to ACE inhibition (i.e. it recurs after ACE inhibitor withdrawal and rechallenge), substitution with an AT 1 -receptor blocker can be considered

23. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – Problem Solving (continued) Worsening renal function: Some increase in urea (blood urea nitrogen), creatinine and K + is to be expected after initiation; if the increase is small and asymptomatic no action is necessary An increase in creatinine of up to 50% above baseline, or 3 mg/dL (266 µmol/L), whichever is the smaller, is acceptable An increase in K +  6.0 mmol/L is acceptable If urea, creatinine or K + rise excessively, consider stopping concomitant nephrotoxic drugs (e.g. NSAIDs), other K + supplements/ K + retaining agents (triamterene, amiloride) and, if no signs of congestion, reducing the dose of diuretic If greater rises in creatinine or K + than those outlined above persist, despite adjustment of concomitant medications, halve the dose of ACE inhibitor and recheck blood chemistry; if there is still an unsatisfactory response, specialist advice should be sought

24. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — ACE INHIBITORS — ACE Inhibitors – Problem Solving (continued) Worsening renal function (cont.): If K + rises to >6.0 mmol/L, or creatinine increases by >100% or to above 4 mg/dL (354 µmol/L), the dose of ACE inhibitor should be stopped and specialist advice sought Blood chemistry should be monitored serially until K + and creatinine have plateaued NOTE: it is very rarely necessary to stop an ACE inhibitor and clinical deterioration is likely if treatment is withdrawn; ideally, specialist advice should be sought before treatment discontinuation

25. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — AT 1 -RECEPTOR BLOCKERS — AT 1 -Receptor Blockers At present, position is unclear due to inconclusive evidence from clinical trials (ELITE I, ELITE II, Val-HeFT) Currently, prescribing AT 1- receptor blockers in heart failure should be confined to patients who are unable to tolerate ACE inhibitors Results from the ongoing CHARM study programme, involving candesartan, should provide a clearer picture of their role in heart failure management

26. Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: Putting Guidelines into Practice — BETA BLOCKERS — McMurray J, Cohen-Solal A, Dietz R, Eichhorn E, Erhardt L, Hobbs R, Maggioni A, Pina I, Soler-Soler J, Swedberg K Eur J Heart Failure 2001;3:495–502

27. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Format The practical recommendations for treatment are reviewed under the following headings:  Why? – what evidence exists to support the use of these treatments  In whom and when? – which patients, what contra-indications, what cautions and drug interactions  Where? – hospital or primary care setting  Which agent and what dose? – options offered based on outcome evidence  How to use – titration and monitoring information  Advice to patient – expected benefits and drawbacks  Problem solving – management of adverse events and concomitant medications

28. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – Why?  USCP, CIBIS II, MERIT-HF and COPERNICUS have shown conclusively that beta-blockers increase survival, reduce hospital admissions and improve NYHA class and quality of life when added to standard therapy (diuretics, digoxin and ACE inhibitors) in patients with stable mild and moderate heart failure and in some patients with severe heart failure One trial (BEST) did not show a reduction in all-cause mortality but did report a reduction in cardiovascular mortality

29. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — United States Carvedilol Program (USCP) Packer M et al. N Engl J Med 1996;334:1349–1355

30. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — ( Cardiac Insufficiency Bisoprolol Study II (CIBIS II) CIBIS II Investigators, Lancet 1999;359:9–13

31. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) Hjalmarson A et al. Lancet 1999;353:2001–2007

32. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – In Whom and When? Indications: Potentially all patients with stable mild and moderate heart failure; patients with severe heart failure should be referred for specialist advice First-line treatment (along with ACE inhibitors) in patients with stable NYHA class II–III heart failure; start as early as possible Contra-indications: Asthma

33. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – In Whom and When? (continued) Cautions/seek specialist advice: Severe (NYHA Class IV) heart failure Current or recent (<4 weeks) exacerbation of heart failure (e.g. hospital admission with worsening heart failure) Heart block or heart rate <60 beats/min Persisting signs of congestion – raised jugular venous pressure, ascites, marked peripheral oedema Drug interactions to look out for: verapamil/diltiazem (should be discontinued) amiodarone

34. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – Where?  In the community in stable patients (NYHA class IV/severe heart failure patients should be referred for specialist advice)  Not in unstable patients hospitalised with worsening heart failure  Other exceptions – see CAUTIONS/SEEK SPECIALIST ADVICE

35. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – Which and What Dose? Starting dose Target dose  bisoprolol 1.25 mg od 10 mg od  carvedilol 3.125 mg bd 25–50 mg bd  metoprolol CR/XL 12.5–25 mg od 200 mg od od = once daily; bd = twice daily

36. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – How to Use Start with a low dose Double dose at not less than two-weekly intervals Aim for target dose or, failing that, the highest tolerated dose Remember some beta-blocker is better than no beta-blocker Monitor HR, BP, clinical status (symptoms, signs – especially signs of congestion, and body weight) Check blood chemistry 1–2 weeks after initiation and 1–2 weeks after final dose titration A specialist heart failure nurse may assist with patient education, follow-up (in person/by telephone) and dose up-titration When to down-titrate/stop up-titration – see PROBLEM SOLVING

37. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – Advice to Patient Explain expected benefits (see WHY?) Emphasise that treatment given as much to prevent worsening of heart failure as to improve symptoms; beta-blockers also increase survival If symptomatic improvement occurs, this may develop slowly, 3–6 months or longer Temporary symptomatic deterioration may occur (estimated 20–30% of cases) during initiation/up-titration phase

38. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – Advice to Patient (continued) Advise patient to report deterioration (see PROBLEM SOLVING) and that deterioration (tiredness, fatigue, breathlessness) can usually be easily managed by adjustment of other medication; patients should be advised not to stop beta-blocker therapy without consulting their physician Patients should be encouraged to weigh themselves daily (after waking, before dressing, after voiding, before eating) and to increase their diuretic dose should their weight increase, persistently (>2 days), by >1.5–2.0 kg

39. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – Problem Solving Worsening symptoms/signs (e.g. increasing dyspnoea, fatigue, oedema, weight gain): If increasing congestion, double the dose of diuretic and/or halve the dose of beta- blocker (if increasing diuretic does not work) If marked fatigue (and/or bradycardia – see below), halve the dose of beta-blocker (rarely necessary) Review patient in 1–2 weeks; if not improved, seek specialist advice If serious deterioration, halve the dose of beta-blocker or stop this treatment (rarely necessary); seek specialist advice

40. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – Problem Solving (continued) Low heart rate: If <50 beats/min and worsening symptoms – halve the dose of beta-blocker or, if severe deterioration, stop beta-blocker (rarely necessary) Review need for other heart-rate slowing drugs (e.g. digoxin, amiodarone, diltiazem) Arrange ECG to exclude heart block Seek specialist advice

41. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — BETA BLOCKERS — Beta Blockers – Problem Solving (continued) Asymptomatic low blood pressure: Does not usually require any change in therapy Symptomatic hypotension: If dizziness, light-headedness and/or confusion and a low blood pressure occur, reconsider need for nitrates, calcium channel blockers and other vasodilators If no signs/symptoms of congestion, consider reducing diuretic dose If these measures do not solve problem, seek specialist advice NOTE: Beta-blockers should not be stopped suddenly unless absolutely necessary (there is a risk of a ‘rebound’ increase in myocardial ischaemia/infarction and arrhythmias); ideally specialist advice should be sought before treatment discontinuation

42. Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: Putting Guidelines into Practice — SPIRONOLACTONE — McMurray J, Cohen-Solal A, Dietz R, Eichhorn E, Erhardt L, Hobbs R, Maggioni A, Pina I, Soler-Soler J, Swedberg K Eur J Heart Failure 2001;3:495–502

43. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Format The practical recommendations for treatment are reviewed under the following headings:  Why? – what evidence exists to support the use of these treatments  In whom and when? – which patients, what contra-indications, what cautions and drug interactions  Where? – hospital or primary care setting  Which agent and what dose? – options offered based on outcome evidence  How to use – titration and monitoring information  Advice to patient – expected benefits and drawbacks  Problem solving – management of adverse events and concomitant medications

44. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Spironolactone – Why? The RALES study showed that low-dose spironolactone increased survival, reduced hospital admissions and improved NYHA class when added to standard therapy (diuretic, digoxin, ACE inhibitor and, in a minority of cases, a beta-blocker) in patients with severe (NYHA class III or IV) heart failure

45. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Pitt B et al. N Engl J Med 1999;10:709–717

46. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Spironolactone – In Whom and When? Indications: Potentially all patients with symptomatically moderately severe or severe heart failure Second-line therapy (after ACE inhibitors and beta-blockers) in patients with NYHA class III–IV heart failure Cautions/seek specialist advice: Significant renal dysfunction (creatinine >221 µmol/L or 2.5 mg/dL) Significant hyperkalaemia (K + >5.0 mmol/L)

47. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Spironolactone – In Whom and When? (Continued) Drug interactions to look out for: ACE inhibitors, AT 1 -receptor blockers, other K + sparing diuretics (beware combination preparations, e.g. frusemide plus amiloride or triamterene), K + supplements (e.g. KCl) NSAIDs ‘Low salt’ substitutes with high K + content

48. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Spironolactone – Where? In the community or in hospital Exceptions – see CAUTIONS/SEEK SPECIALIST ADVICE Spironolactone – Which Dose? Starting dose: 25 mg od or on alternate days Target dose:25–50 mg od

49. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Spironolactone – How to Use Start at 25 mg once daily Check blood chemistry at 1, 4, 8 and 12 weeks; 6, 9 and 12 months; 6 monthly thereafter If K + rises to between 5.5 and 6.0 mmol/L, or creatinine rises to 2.5 mg/dL (221 µmol/L), reduce dose to 25 mg on alternate days and monitor blood chemistry closely If K + rises to >6.0 mmol/L, or creatinine to >4.0 mg/dL (354 µmol/L), stop spironolactone and seek specialist advice

50. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Spironolactone – Advice to Patient Explain expected benefits (see WHY?) Treatment is given to improve symptoms, prevent worsening of heart failure and to increase survival Symptom improvement occurs within a few weeks to a few months of starting treatment Avoid NSAIDs not prescribed by a physician (self-purchased ‘over the counter’ treatment, e.g. ibuprofen) Temporarily stop spironolactone if diarrhoea and/or vomiting occur and contact physician

51. Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice — SPIRONOLACTONE— Spironolactone – Problem Solving Worsening renal function/hyperkalaemia: See HOW TO USE section Major concern is hyperkalaemia (K + >6.0 mmol/L) though this was uncommon in RALES; a high-normal K + may be desirable in heart failure patients, especially if taking digoxin It is important to avoid other K + retaining drugs (e.g. K + sparing diuretics) and nephrotoxic agents (e.g. NSAIDs) Some ‘low salt’ substitutes have a high K + content Male patients may develop breast discomfort and/or gynaecomastia